B lymphocytes (also referred to as B cells) mature within the bone marrow and leave the marrow expressing a unique antigen-binding membrane receptor. The B-cell receptor is a membrane-bound immunoglobulin glycoprotein. When a B cell encounters the antigen for which its membrane-bound antibody is specific, the cell begins to divide very rapidly; its progeny differentiate into memory B cells and effector cells called plasma cells. Memory B cells have a longer lifespan and continue to express membrane-bound antibody with the same specificity as the original parent cell. Plasma cells do not produce membrane-bound antibody but instead produce the antibody in a form that can be secreted.
Immunologic tolerance is a specific state of non-responsiveness to an antigen. Immunologic tolerance generally involves more than the absence of an immune response; this state is an adaptive response of the immune system, one meeting the criteria of antigen specificity and memory that are the hallmarks of any immune response. Tolerance develops more easily in fetal and neonatal animals than in adults, suggesting that immature T and B cells are more susceptible to the induction of tolerance. Moreover, studies have suggested that T cells and B cells differ in their susceptibility to tolerance induction. Induction of tolerance, generally, can be by clonal deletion or clonal anergy. In clonal deletion, immature lymphocytes are eliminated during maturation. In clonal anergy, mature lymphocytes present in the peripheral lymphoid organs become functionally inactivated.
Treatment of transplant and autoimmune patients often includes suppression of lymphocyte activation by tacrolimus (FKS506) or cyclosporin, both inhibitors of calcineurin. Borel, et al., (1976) Agents Actions 6: 468-75; Kino et al., (1987) J. Antibiot. (Tokyo) 40, 1256-65; Ho, et al, (1996) Clin. Immunol. Immunopathol. 80, S40-5; and Ruhlmann and Nordheim, (1997) Immunobiology 198, 192-206. While effective during therapy, these compounds do not allow (re-)establishment of immunological tolerance to the offending autoantigen and instead can inhibit tolerance induction. Prud'homme and Vanier, (1993) Clin. Immunol. Immunopathol. 66:185-92. Accordingly, the development of drugs that could induce tolerance would be desirable.
Therefore, it is an object of this invention to identify the expression profiles which are unique to B-cell tolerance, activation and immunosuppression. It is further an object to use the expression profiles in assays to identify agents which can be used in the modulation of B cell activity including B cell tolerance, activation, immunosuppression, mitosis, apoptosis, differentiation and migration. It is further an object to use the expression profiles as diagnostics to identify B cells which are abnormal. It is further an object to provide assays to identify agents for the treatment of B cell related disorders.